Cholesterol Lowering and CV Risk Metaanalyses OnTreatment LDL

Cholesterol Lowering and CV Risk: Meta-analyses

On-Treatment LDL and CHD Events in Statin Trials 30 4 S - PBO Event rate (%) Secondary Prevention 4 S - Rx 20 LIPID - PBO CARE - PBO LIPID - Rx HPS - PBO CARE - Rx HPS - Rx 10 TNT - ATV 10 PROVE-IT - PRA TNT - ATV 80 PROVE-IT - ATV 80 Primary Prevention WOSCOPS - PBO AFCAPS - Rx WOSCOPS - Rx ASCOT - PBO ASCOT - Rx 0 40 (1. 0) 60 70 80 (1. 6) (1. 8) (2. 1) 100 (2. 6) 120 (3. 1) 140 (3. 6) 160 (4. 1) 180 (4. 7) 200 (5. 2) LDL-C achieved, mg/d. L (mmol/L) Adapted from Rosenson RS. Expert Opin Emerg Drugs. 2004; 9: 269 -279. La. Rosa JC et al. N Engl J Med. 2005; 352: 1425 -1435. 2

Second Cycle of the CTT Meta-analysis: Proportional Effects on Major Vascular Events Per Mmol/L LDL-C Reduction No. of events (% pa) Statin/more Relative risk (CI) per mmol/L LDL-C reduction Control/less More vs. less statin PROVE-IT A to Z TNT IDEAL SEARCH Subtotal (5 trials) 406 (11. 3) 257 (7. 2) 889 (4. 0) 938 (5. 2) 1347 (3. 6) 3837 (4. 5) 458 (13. 1) 282 (8. 1) 1164 (5. 4) 1106 (6. 3) 1406 (3. 8) 4416 (5. 3) 5883 (3. 1) 254 (5. 4) 144 (9. 0) 114 (2. 7) 102 (0. 5) 105 (0. 5) 172 (2. 2) 362 (8. 1) 7136 (2. 8) 7467 (4. 0) 293 (6. 4) 162 (10. 1) 136 (3. 3) 140 (0. 7) 194 (1. 0) 174 (2. 2) 368 (8. 3) 8934 (3. 6) 10973 (3. 2) 13350 (4. 0) 0. 72 (0. 66 - 0. 78) P < 0. 001 Statin vs. control First cycle (14 trials) ALLIANCE 4 D ASPEN MEGA JUPITER GISSI-HF AURORA Subtotal (21 trials) Total (26 trials) 99% or 95% CI Difference between more vs. less and statin vs. control: c 2= 4. 5, p=0. 03 0. 78 (0. 76 - 0. 81) 0. 5 0. 75 Statin/more better 1 0. 79 (0. 77 - 0. 81) P < 0. 001 0. 78 (0. 76 - 0. 80) P < 0. 001 1. 25 1. 5 Control/less better 1 Cholesterol Treatment Trialists Collaboration. Lancet. 2010; 376: 1670 -1681. 3

Second Cycle of the CTT Meta-analysis: More vs Less Statin—Proportional Effects on Major Vascular Events Per Mmol/L LDL-C Reduction No. of events (% pa) More statin Less statin Relative risk (CI) per mmol/L LDL-C reduction 1175 (1. 3%) 1380 (1. 5%) 0. 71 (0. 58 - 0. 87) 645 (0. 7%) 694 (0. 7%) 0. 85 (0. 63 - 1. 15) 1725 (1. 9%) 1973 (2. 2%) 637 (0. 7%) 731 (0. 9%) 0. 74 (0. 65 - 0. 85) P < 0. 0001 0. 72 (0. 55 - 0. 95) PTCA Unspecified 1166 (1. 3%) 1508 (1. 8%) 0. 60 (0. 50 - 0. 71) 447 (0. 5%) 502 (0. 6%) 0. 78 (0. 58 - 1. 04) Any coronary revascularization 2250 (2. 6%) 2741 (3. 2%) 440 (0. 5%) 526 (0. 6%) 0. 66 (0. 60 - 0. 73) P < 0. 0001 0. 69 (0. 50 - 0. 95) 69 (0. 1%) 57 (0. 1%) 1. 39 (0. 57 - 3. 39) 63 (0. 1%) 80 (0. 1%) 0. 63 (0. 24 - 1. 66) 572 (0. 6%) 663 (0. 7%) 3837 (4. 5%) 4416 (5. 3%) 0. 74 (0. 59 - 0. 92) P = 0. 007 0. 72 (0. 66 - 0. 78) Nonfatal MI CHD death Any major coronary event CABG Ischemic stroke Hemorrhagic stroke Unknown stroke Any major vascular event (5 trials) 99% or 95% CI 0. 5 0. 75 More statin better Cholesterol Treatment Trialists Collaboration. Lancet. 2010; 376: 1670 -1681. 1 1. 25 1. 5 Less statin better 4

Second Cycle of the CTT Meta-analysis: Statin vs Control—Proportional Effects on Major Vascular Events Per Mmol/L LDL-C Reduction No. of events (% pa) Statin Control Relative risk (CI) per mmol/L LDL-C reduction Nonfatal MI 2310 (0. 9%) 3213 (1. 2%) 0. 74 (0. 69 - 0. 78) CHD death Any major coronary event 1242 (0. 5%) 1587 (0. 6%) 0. 80 (0. 73 - 0. 86) 3380 (1. 3%) 4539 (1. 7%) CABG 816 (0. 3%) 1126 (0. 4%) 0. 76 (0. 73 - 0. 79) P < 0. 001 0. 76 (0. 69 - 0. 83) PTCA Unspecified 601 (0. 2%) 775 (0. 3%) 0. 78 (0. 69 - 0. 89) 1686 (0. 6%) 2165 (0. 8%) 0. 76 (0. 70 - 0. 83) Any coronary revascularization 3103 (1. 2%) 4066 (1. 6%) Ischemic stroke Hemorrhagic stroke 987 (0. 4%) 1225 (0. 5%) 0. 76 (0. 73 - 0. 80) P < 0. 001 0. 80 (0. 73 - 0. 88) 188 (0. 1%) 163 (0. 1%) 1. 10 (0. 86 - 1. 42) Unknown stroke Any stroke 555 (0. 2%) 629 (0. 2%) 0. 88 (0. 76 - 1. 02) 1730 (0. 7%) 2017 (0. 8%) 7136 (2. 8%) 8934 (3. 6%) 0. 85 (0. 80 - 0. 90) P < 0. 001 0. 79 (0. 77 - 0. 81) P < 0. 001 Any major vascular event (all 21 trials) 99% or 95% CI 0. 5 0. 75 Statin better Cholesterol Treatment Trialists Collaboration. Lancet. 2010; 376: 1670 -1681. 1 1. 25 1. 5 Control better 5

Meta-analysis of Statin Trials and Fatal and Nonfatal Stroke N = 165, 732 Study Active group Control group (%) RR (95% CI) Primary prevention of stroke SEARCH JUPITER ASPEN MEGA IDEAL TNT ALLIANCE CARDS PROVE-IT A TO Z ASCOT-LLA ALLHAT-LLT GREACE HPS (with no prior CVD) PROSPER MIRACL GISSI AFCAPS/Tex. CAPS LIPID (with no prior CVD) Post-CABG CARE (with no prior CVD) WOSCOPS SSSS 4. 2 0. 4 2. 8 1. 3 3. 4 2. 3 2. 9 1. 5 1. 0 1. 2 1. 7 4. 0 1. 2 3. 2 4. 7 0. 8 0. 9 0. 4 3. 3 2. 6 1. 9 1. 4 2. 5 0. 91 (0. 77, 1. 08) 0. 52 (0. 34, 0. 78) 0. 89 (0. 56, 1. 40) 0. 83 (057, 1. 20) 0. 87 (0. 70, 1. 08) 0. 76 (0. 60, 0. 96) 0. 90 (0. 58, 1. 42) 0. 53 (0. 31, 0. 90) 1. 09 (0. 59, 2. 01) 0. 79 (0. 48, 1. 29) 0. 73 (0. 56, 0. 96) 0. 91 (0. 76, 1. 09) 0. 53 (0. 24, 1. 18) 0. 67 (0. 57, 0. 77) 1. 04 (0. 82, 1. 31) 0. 50 (0. 25, 1. 00) 1. 05 (0. 56, 1. 96) 0. 82 (0. 41, 1. 67) 0. 84 (0. 67, 1. 05) 1. 12 (0. 58, 2. 18) 0. 67 (0. 44, 1. 01) 0. 90 (0. 61, 1. 34) 0. 72 (0. 51, 1. 01) 4. 6 0. 7 3. 2 1. 6 3. 9 3. 1 3. 2 2. 8 0. 9 1. 6 2. 4 4. 5 2. 1 4. 8 4. 5 1. 6 0. 9 0. 5 3. 9 2. 4 2. 8 1. 5 3. 5 Sub-total: P < 0. 0001 (heterogeneity: I 2 = 26. 6%, P = 0. 12) 0. 81 (0. 75, 0. 87) Secondary prevention of stroke SPARCL HPS (with prior CVD LIPID (with prior CVD) CARE (with prior CVD) 11. 2 10. 3 9. 5 13. 1 10. 4 13. 3 20. 0 0. 85 (0. 73, 0. 99 (0. 81, 1. 21) 0. 72 (0. 46, 1. 12) 0. 68 (0. 37, 1. 25) Sub-total: P = 0. 03 (heterogeneity: I 2 = 0. 8%, P = 0. 39) 0. 88 (0. 78, 0. 99) 0. 82 (0. 77, 0. 87 Total: P < 0. 0001 (heterogeneity: I 2 = 7. 3%, P = 0. 36) Amarenco P et al. Lancet Neurol. 2009; 8: 453 -463. 0. 1 0. 2 0. 5 1 2 Log-scale 5 10 6

Meta-analysis of Statin Trials and Stroke Mortality Study Active group (%) Control group (%) RR (95% CI) Primary prevention of stroke SEARCH JUPITER CARDS ALLHAT-LLT GREACE HPS PROSPER MIRACL GISSI LIPID CARE WOSCOPS SSSS 0. 9 0. 3 0. 1 1. 0 0. 9 0. 8 0. 2 0. 5 0. 2 0. 6 1. 1 0. 7 0. 5 1. 1 0. 1 1. 2 0. 5 0. 1 0. 2 0. 6 0. 1 0. 5 0. 85 (0. 60, 1. 21) 0. 50 (0. 13, 2. 00) 0. 14 (0. 02, 1. 15) 0. 95 (0. 65, 1. 38) 0. 33 (0. 01, 8. 17) 0. 81 (0. 62, 1. 05) 1. 58 (0. 81, 3. 09) 1. 51 (0. 25, 9. 02) 1. 00 (0. 25, 3. 98) 0. 81 (0. 46, 1. 43) 4. 99 (0. 58, 42. 70) 1. 50 (0. 42, 5. 30) 1. 17 (0. 54, 2. 52) 0. 90 (0. 76, 1. 05) Sub-total: P = 0. 18 (heterogeneity: I 2 = 0%, P = 0. 48) Secondary prevention of stroke SPARCL 1. 0 1. 7 0. 59 (0. 36, 0. 97) Total: P = 0. 10 (heterogeneity: I 2 = 8. 1%, P = 0. 36) 0. 1 0. 2 Amarenco P et al. Lancet Neurol. 2009; 8: 453 -463. 0. 87 (0. 73, 1. 03) 0. 5 1 2 Log-scale 5 10 7

Stroke Risk and LDL Lowering in Statin Trials N = 165, 732 Relative Risk of Stroke in Active vs Control Groups (non-log scale) Each 1 mmol (39 mg) LDL-C reduction reduced the risk of stroke by 21% (95% CI, 6. 3– 33. 5%; p<0. 009) 1. 2 Post-CABG 1. 1 PROVE-IT PROSPER GISSI ALLHAT-LLT SEARCH WOSCOPS IDEAL ASPEN LIPID ALLIANCE AFCAPS/Tex. CAPS MEGA A to Z ASCOT-LLA TNT HPS SSSS CARE 1. 0 0. 9 0. 8 0. 7 0. 6 SPARCL-CS (-) SPARCL-CS (+) CARDS 0. 5 JUPITER GREACE MIRACL 0. 4 0 0 -15 -20 -25 -30 -35 -40 -45 -50 -55 Between Group Difference in LDL-Cholesterol Reduction, % (active minus control groups) Amarenco P et al. Lancet Neurol. 2009; 8: 453 -463. 8

Second Cycle of the CTT Meta-analysis: Proportional Effects on Cause-Specific Mortality Per Mmol/L LDL-C Reduction No. of deaths(% pa) Statin/more Control/less Relative risk (CI) per mmol/L LDL-C reduction Vascular causes 1887 (0. 5%) 1446 (0. 4%) 3333 (0. 9%) 2281 (0. 6%) 1603 (0. 4%) 3884 (1. 1%) 0. 80 (0. 74 - 0. 87) 0. 89 (0. 81 - 0. 98) 0. 84 (0. 80 - 0. 88) Ischemic stroke Hemorrhagic stroke Unknown stroke Stroke 153 (0. 0%) 102 (0. 0%) 228 (0. 1%) 483 (0. 1%) 139 (0. 0%) 89 (0. 0%) 273 (0. 1%) 501 (0. 1%) 1. 04 (0. 77 - 1. 41) 1. 12 (0. 77 - 1. 62) 0. 85 (0. 66 - 1. 08) 0. 96 (0. 84 - 1. 09) Other vascular 404 (0. 1%) 409 (0. 1%) 0. 98 (0. 81 - 1. 18) Any vascular 4220 (1. 2%) 4794 (1. 3%) 0. 86 (0. 82 - 0. 90) 1781 (0. 5%) 224 (0. 1%) 127 (0. 0%) 811 (0. 2%) 2943 (0. 8%) 1798 (0. 5%) 237 (0. 1%) 127 (0. 0%) 832 (0. 2%) 2994 (0. 8%) 0. 99 (0. 91 - 1. 09) 0. 88 (0. 70 - 1. 11) 0. 98 (0. 70 - 1. 38) 0. 96 (0. 83 - 1. 10) 0. 97 (0. 92 - 1. 03) 479 (0. 1%) 539 (0. 1%) 0. 87 (0. 76 - 0. 99) 7642 (2. 1%) 8327 (2. 3%) 0. 90 (0. 87 - 0. 93) CHD Other cardiac All cardiac Nonvascular Cancer Respiratory Trauma Other nonvascular Any nonvascular Unknown death Any death 99% or 95% CI Cholesterol Treatment Trialists Collaboration. Lancet. 2010; 376: 1670 -1681. 0. 5 0. 75 Statin/more better 1 1. 25 1. 5 Control/less better 9

Meta-analysis of Statin Trials: Effect of Intensive LDL-C Lowering vs Standard Statin Therapy on Fatal and Nonfatal Stroke Study SEARCH IDEAL TNT ALLIANCE PROVE-IT A to Z Intensive arm (%) Conventional arm (%) 4. 2 3. 4 2. 3 2. 9 1. 0 1. 2 4. 6 3. 9 3. 1 3. 2 0. 9 1. 6 RR (95% CI) 0. 91 (0. 77, 1. 08) 0. 87 (0. 70, 1. 08) 0. 76 (0. 60, 0. 96) 0. 90 (0. 58, 1. 42) 1. 09 (0. 59, 2. 01) 0. 79 (0. 48, 1. 29) Total: P = 0. 009 (heterogeneity: I 2 = 0%, P = 0. 80) 0. 1 0. 2 Amarenco P et al. Lancet Neurol. 2009; 8: 453 -463. RR (95% CI) 0. 87 (0. 78, 0. 96) 0. 5 1 2 Log-scale 5 10 10